Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/). This FOA will be administered by the National Human Genome Research Institute (NHGRI) (http://www.nhgri.nih.gov/) and Office of Research Infrastructure Programs (http://www. http://dpcpsi.nih.gov/orip/index) on behalf of the NIH (http://www.nih.gov/). Other participating Institutes include:

National Cancer Institute (NCI)
National Eye Institute (NEI)
National Heart, Lung, and Blood Institute (NHLBI)
National Human Genome Research Institute (NHGRI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Deafness and Other Communication Disorders (NIDCD)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute on Drug Abuse (NIDA)
National Institute of Environmental Health Sciences (NIEHS)
National Institute of Neurological Disorders and Stroke (NINDS)
Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP)
Office of Research on Women’s Health (ORWH)

Funding Opportunity Title

Limited Competition: Knockout Mouse Production and Phenotyping Project (UM1) 

Activity Code

UM1 Research Project with Complex Structure Cooperative Agreement

Announcement Type

Reissue of RFA-RM-10-013 and RFA-RM-10-011

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-RM-15-017  

Companion Funding Opportunity

RFA-RM-15-016, UM1 Research Project with Complex Structure Cooperative Agreement

Number of Applications

Only one application per institution is allowed, as defined in Section III.3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.310, 93.866; 93.867; 93.847; 93.856; 93.855; 93.172; 93.273; 93.233; 93.839; 93.838; 93.837; 93.113; 93.865; 93.396; 93.279; 93.313; 93.173; 93.846; 93.853; 93.121; 93.351

Funding Opportunity Purpose

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress. The purpose of this FOA is to solicit applications for research projects to make maximum progress toward the goal of producing a null-mutant mouse phenotype resource for each gene in mouse strain C57BL/6, for the purpose of elucidating functional information for each protein-coding gene in the mammalian genome. The specific objectives of this FOA are to generate mutant mouse lines using CRISPR/Cas9 technology, perform phenotyping assays, conduct quality control assessments, cryopreserve germplasm, and make mice and data readily available to the research community. The mouse is the ideal mammalian system in which to produce a functional genomics resource because of the long history and depth of understanding of mouse genetics, the sophistication of assistive reproductive technology in the mouse system, short generation times, and the low cost of working with mice in comparison to other mammals. The recent breakthroughs in CRISPR/Cas9 technology make the mouse an even more cost effective model system and will drive technology of mouse production. The goal of this FOA is to support high-throughput broad based phenotyping of approximately 600 null-mutant mouse lines per year, with an overall goal of 3,000 lines for this five-year project period of the Knockout Mouse Phenotyping Program (KOMP2).  

Key Dates
Posted Date

October 7, 2015

Open Date (Earliest Submission Date)

November 9, 2015  

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

December 9, 2015, by 5:00 PM local time of applicant organization. All types of applications allowed for this funding opportunity announcement are due on this date.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March, 2016

Advisory Council Review

May 2016

Earliest Start Date

August 2016

Expiration Date

December 10, 2015

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement
Section I. Funding Opportunity Description

Background

More than 12 years have passed since the completion of the Human Genome Project, yet we remain largely ignorant about the function of most genes in the mammalian genome. In fact, the function of at least half of the mammalian genes is poorly understood; nearly one third have no functional annotation. In 2011 it was reported that 75% of protein research continues to focus on the 10% of proteins that were known before the genome was sequenced) Barriers to understanding the function of ‘dark’ protein-coding genes include lack of tools and lack of funding mechanisms to support tool development and characterization. Defining the functional role of the complete set of protein-coding genes will have a transformative effect on biology and the understanding of human disease but cannot be achieved with the traditional hypothesis-driven research approach.

The mouse has long been an important mammalian model system for the study of gene function in human health and disease, and the premiere embodiment of that is the ability to generate knockout (KO) mice. Mouse mutants with phenotypes mimicking human traits are critical research tools for understanding the genetics underlying mammalian biology. Equally important, mouse mutants have been the tools used to begin to understand gene function and pathways as the field has moved from gene identification to mammalian functional genomics.

There have been a number of international efforts that worked to develop a comprehensive KO mouse resource. Following a March 2005 workshop that endorsed the concept (http://www.genome.gov/15014549), the NIH launched the Knockout Mouse Program (KOMP) to generate mutations in 8,500 genes in the C57BL/6 strain by deleting all or most of the exons in target genes or by making knockout-first conditional ready alleles. By the end of 2011, KOMP had completed the goal of producing 8,500 mutant ES cell lines. In parallel, the European Conditional Mouse Mutagenesis Program (EuCOMM) and the North American Conditional Mouse Mutagenesis Program (NorCOMM) accomplished their goals of producing an additional 9,000 mutant strains. The three programs coordinated their efforts through the International Knockout Mouse Consortium (IKMC) to produce a comprehensive resource of mutant mouse embryonic stem (ES) cell lines representing over 17,000 unique genes. In 2006, the NIH established a repository to archive, maintain, and distribute ES cell clones, as well as live mouse lines, frozen embryos and sperm, and vectors (www.komp.org). To date, the KOMP Repository has delivered over 31,000 products (vectors, ES cell lines, mice, and services) representing over 5,000 unique genes, which is a strong indication of the community’s valuation of the program.

The first large-scale phenotyping effort using IKMC ES cells was funded by the European Commission (EC) in 2008. The European Mouse Disease Clinic (EUMODIC, http://www.eumodic.org/) program was comprised of 4 mouse phenotyping centers, with the goal to provide phenotype information on 500 IKMC knockout mouse lines using a common phenotyping protocol developed by the European Mouse Phenotyping Resource of Standardised Screens (EMPReSS, http://empress.har.mrc.ac.uk/). The NIH held a KOMP Phenotyping Conference in Bethesda, MD in October 2009, at which a group of researchers representing diverse scientific backgrounds expressed their unanimous enthusiasm and support for a proposed effort to conduct high-throughput and comprehensive phenotyping of the resource being produced by the members of the IKMC (meeting report available at www://www.komp.org). The phenotyping data would be released rapidly and freely to the public as they are generated, with the mice being archived for distribution to the research community. The meeting participants stressed that any U.S. phenotyping effort must be coordinated with comparable efforts elsewhere (similar discussions and plans were being made in Europe, Canada, and Asia). The standard phenotyping tests, analyses, and examinations included in the KOMP resource effort should be chosen primarily on the basis of their reliability, power, and likelihood to reveal disease and human clinical relevance. These recommendations were highly similar to those that came from other efforts to solicit input from the US national research community.

Subsequently, the Knockout Mouse Phenotyping Program (KOMP2) was launched in the fall of 2011. Three mouse production and cryopreservation centers were funded and tasked with converting IKMC knockout ES cells into mice for phenotyping. These centers had the additional responsibility of making a preliminary determination of whether the null mutation affected the fertility or embryonic development of the mice. Three phenotyping centers were funded and assigned the task of broad based phenotyping. The funded centers were required to work together to identify a common set of core assays that were performed similarly across all centers using “harmonized” conditions. The final component of KOMP2 was the inclusion of the data coordination center and database to track progress, perform Quality Control (QC) and other analyses on the phenotype data, and disseminate this information to the research community. Presently, the KOMP2 research network has completed production of 2,500 strains, and is on track to complete the phenotyping project in the fall of 2016.

At its launch, KOMP2 integrated operations with other members of the International Mouse Phenotyping Consortium (IMPC, http://www.mousephenotype.org/). It is expected that the successful applicants to this FOA will coordinate their efforts with the other units of the KOMP2 research network and with the IMPC to identify knockout lines to be phenotyped, harmonize phenotyping platforms, continue data integration and analysis, and make use of prior know-how and experience.

Research Objective

This FOA will support work to design and produce null mutant mice and phenotype them. The ability to alter genes directly in mouse zygotes has been advanced recently by the use of CRISPR/Cas9 technology. Optimizing CRISPR/Cas9 technology for use in the KOMP2 project has the potential to dramatically enhance production throughput while reducing overall costs, putting the overall goal of the IMPC project (to knockout and phenotype the majority of the genes in the mouse genome) within reach. Thus, it is expected that centers will adapt CRISPR technology for production of null alleles in a high throughput pipeline. In addition, this FOA will support further technology development to enable production of complex alleles. This FOA seeks to fund centers with a strong history in high throughput knockout mouse production, a history of working in cooperative large-scale projects, an ability to be innovative and adaptive to new technologies and an ability to meet production standards and goals. Assuming three centers are funded, the specific objectives of this FOA are to generate at least 250 mutant mouse lines per center each year during the first 4 years, presumably using CRISPR/Cas9 technology, and deposit these mice at the Mutant Mouse Regional Resource Center (MMRRC) repositories. Furthermore, the centers will undertake broad based phenotyping of mice at embryonic, juvenile, and adult ages. Specifically, for strains harboring mutations that cause embryonic lethality, mice will be examined using IMPC approved procedures (http://www.mousephenotype.org/impress).  Examination of other strains should follow IMPC approved procedures for phenotyping juvenile mice (up to 16 weeks of age). Finally, the FOA is intended to support pilot phenotyping activities using older mice (age 12-18 months).

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

Renewal

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

Issuing IC and partner components intend to commit an estimated total of $85,175,000 to fund 2-3 awards.

Award Budget

Application budgets are not limited but need to reflect the actual needs of the proposed project.

Award Project Period

The total project period may not exceed five years.    

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

Only grantees funded under the KOMP2 Knockout Mouse Production and Cryopreservation (U42) and Knockout Mouse Phenotyping (U54) are eligible to apply.

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.   

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility
Number of Applications

Only one application per institution (normally defined by having a unique DUNS number or NIH IPF number) is allowed.

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
Section IV. Application and Submission Information
1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

The Research Strategy should consist of the following sub-sections with the indicated page limits:

  • Overall Goals Section: one required – 6 pages
  • Animal Production and Cryopreservation Section: one required – 12 pages
  • Phenotyping Section: one required – 12 pages
  • Research Management Plan: one required – 6 pages
Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed. 

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed. The PD/PI is required to devote at least 20% effort (2.4 months) to the award.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.  

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 

Research Strategy: The Research Strategy should consist of the following subsections, uploaded as a single pdf attachment.

A) Overall Goals Section

B) Animal Production and Cryopreservation Section

C) Phenotyping Section

D) Research Management Plan

A) Overall Goals Section

State concisely the goals of the proposed project and summarize the expected outcome(s), including the impact that the results of the proposed Production and Phenotyping center will exert on KOMP2 and the research field(s) that it encompasses.

Describe briefly the purpose and history of KOMP2 and the applicant’s mouse production and phenotyping contributions to the research network. Describe overall design, development, and advancement of the production and phenotyping, provide a general overview of how the resources generated by the project have been made available rapidly and efficiently to the biomedical community. Describe how prior KO mouse production and phenotyping efforts have served the needs of investigators in a variety of research areas.

The application should then describe the organization of the proposed center and its management structure, including integration of the components to maintain efficient operation, key personnel, and reporting relationships. Furthermore, the application should describe how the center would be integrated into the broad based phenotyping activity of the whole KOMP2 research network. In addition, describe proposed methods to utilize innovative technologies and improve the efficiency of generating knockout mice and quality of the cryopreserved germ cells.

B) Animal Production and Cryopreservation Section

State concisely the goals of the proposed Animal Production and Cryopreservation Section and summarize the expected outcome(s), including the impact that the results of this Section will exert on the center with regard to capacity and throughput.

Progress Report: A detailed report describing activities related to reliable, high throughput production of high-quality knockout strains, and their cryopreservation, during the last 4 years should be included. The applicant should describe experience with adapting CRISPR/Cas9 technology to generate knockout strains in a high-throughput environment, and provide a comparison to traditional use of ES cells. Include a description of the expertise and training of non-Key Personnel technical staff to perform relevant procedures (e.g., microinjection technician, etc.).

Gene Selection: The target gene selection strategies should be described in detail; it is expected that each center will generate at least 250 germline-confirmed knockout mouse lines per year (to reach at least 1,000 lines over the first 4 years), with a preference for genes that have little or no annotation. The applicant should describe a strategy to define and identify genes that are “poorly annotated.” In addition, the application should describe a strategy to minimize overlap among centers.

Knockout Animal Production and Breeding Cohorts for a Phenotyping Pipeline: The proposed plan should describe project management and how various units of the center will be integrated; more specifically, describe the design and development of the CRISPRs/Cas9 technology based production pipeline, its capacity and presence of required expertise. The plan should have clear descriptions of the procedures for efficient generation of defined deletions in N1 mice, guide RNA design, microinjection procedures, mutation screening methods, animal breeding schemes, and workflows for scaled mouse production. Strategies for analysis of off-target sites identified by established algorithms for genome-wide analysis of guide mismatch should be presented. The plan should include assessment and statistical analysis of embryonic lethality, fertility and fecundity of homozygous mice. Centers should establish and expand breeding colonies to produce homozygous or (for lethal or subviable lines) heterozygous mice and provide them as cohorts to the phenotyping pipelines.

Finally, applicants should present:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well as proposed solutions or alternatives;

iii. timelines and quantitative milestones where appropriate

Information Technology: The applicant should discuss all pertinent informatics issues. These include, but are not limited to, the informatics infrastructure of the production system, such as the basic IT infrastructure/system administration, the laboratory information management system, and the system for data handling and deposition. It is vital that the production data be provided in a format that can be easily uploaded to the DCC. It is expected that the data uploads will include sufficient tracking information to assure that project goals are being met. Recently, the current KOMP2 database has been extensively revised to accommodate new production technology and workflows. Specifically, new tools and technologies include a suite of CRISPR analysis tools that allow for the selection of gene targets, uploading of quality control data, sequence traces and tracking of resulting mutant alleles. All these activities should lead to the timely uploads of the data and should be coordinated with data wranglers at the Data Coordinating Center (DCC).  The application should describe how data submission procedures would accommodate the IMPC required data format and submission at determined frequencies.

Cryopreservation: The applicant should describe methods for cryopreservation of generated mouse strains after demonstration of successful germline transmission of knockout mutations. Methods can include, but not necessarily be limited to, cryopreservation of sperm and/or embryos. Techniques and associated QC should be sufficiently robust so as to allow direct deposition of cryopreserved germplasm in repositories. The timeline from production to availability in a repository must be discussed. 

Quality Control: The applicant should discuss any steps that will be taken to determine and ensure the quality of, or otherwise validate the resources that will be generated, beyond those mentioned above. Examples of appropriate quality control procedures include those for a) identification of the targeted allele; b) testing for genetic mosaicism; c) definition of the range of deletions; d) demonstration that no undesired alterations have occurred at the site of mutation; e) determination of the stability of the integration and the copy number of the vector sequence (if relevant); f) defining efficiency of embryo or sperm cryopreservation and cryo-recovery; and g) testing the pathogen status of biological reagents. The applicant should discuss briefly their proposed animal husbandry conditions, approaches to monitor animal health, and their experience in producing standardized mice to be phenotyped. Evidence of the effectiveness of the proposed quality control programs should be included.  

Technology Development: Provide documentation of experience in developing and applying new and improving extant technologies for mouse production, distribution, and cryopreservation. Describe how a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, or instrumentation will be achieved. Describe how technology improvements will increase the efficiency and decrease the cost of high-throughput production processes. The cost of any proposed technology development should be justified in terms of the technology’s effect in reducing production costs. The cost of such technology development should be included in the overall production cost on a “per knockout” basis.

For example, continued optimization of CRISPR/Cas9 technology is particularly relevant. This could include improving efficiency of the procedures such as prediction and testing of the off-targets effects, decreasing mosaicism, simultaneous injection of guides for multiple target gene modifications, and further improvement of the screening tools. The plan should address concepts for how to expand CRISPR/Cas9 technology for generation of more complex alleles, such as conditional and/or reporter null.  If simultaneous generation of a conditional allele will be possible for minor additional cost, a cost model should be included. Other examples include effective implementation of machine-readable tags for individual mouse tracking and monitoring and further development of cryopreservation technologies and increasing efficiency of cryo-recovery.

C) Phenotyping Section

State concisely the goals of the proposed Phenotyping Section and summarize the expected outcome(s), including the impact that the results of this Section will exert on the whole center.

Progress Report: A detailed progress report describing activities related to high-throughput phenotyping of knockout strains for the last 4 years should be included. The applicant should describe the number of phenotype assays performed per month during this time period, design of pipeline, rationale for cohort size of mutants and controls, and any other internal metrics that the applicant has found to be useful in evaluating and managing the phenotyping of mice. Include a description of the expertise and training for staff to perform phenotyping assays (e.g., veterinary pathologist for necropsy and histopathology; radiologist for analysis of MRI or PET scan) and the ability to ramp up as needed to complete the goals of this application.

Embryo Phenotyping: The applicant should describe in detail the phenotyping assays to be employed, as well as relevant experience and expertise. The current approved IMPC pipeline (http://www.mousephenotype.org/impress) should be used as a template for the phenotyping pipeline. The applicant should address the process and/or ability to perform standard IMPC phenotyping assays, including the size of cohorts needed for each assay, the timing of the tests, and the source and numbers of wild type mice needed for controls in the phenotyping assays.

The ability to harmonize phenotyping platforms and cooperate with the international efforts is an important criterion for evaluation of the applications. Included in this is the flexibility to add, modify or drop tests as the project progresses. The applicants should address their ability to adopt new procedures. Relevant to this issue, the applicant can propose, with adequate scientific justification, modifications to the standard pipeline.

All phases of the phenotyping process must be addressed as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well as proposed solutions;

iii. stages of embryo analysis and any triage decision methodologies;

iv. imaging modalities utilized at each stage (e.g., OPT, microCT, etc.);

v. data capture, image analysis and data storage systems and methods;

vi. timelines and quantitative milestones where appropriate

Juvenile Phenotyping: The applicant should describe in detail the phenotyping assays to be employed, as well as relevant experience and expertise. The current approved IMPC pipeline (http://www.mousephenotype.org/impress) should be used as a template for the phenotyping pipeline. The applicant should address the process and/or ability to perform standard IMPC phenotyping assays, including the size of cohorts needed for each assay, the timing of the tests, and the source and numbers of wild type mice needed for controls in the phenotyping assays.

The ability to harmonize phenotyping platforms and cooperate with the international efforts is an important criterion for evaluation of the applications. Included in this is the flexibility to add, modify or drop tests as the project progresses. The applicants should address their ability to adopt new procedures. Relevant to this issue, the applicant can propose, with adequate scientific justification, modifications to the standard pipeline.  A cost benefit analysis of phenotyping assays, including hit rates and clinical relevance, is encouraged to justify inclusion or dropping assays from the current and proposed pipelines.  A genomics approach to phenotyping is highly desirable if cost effective.  Thus, applicants are encouraged to submit applications inclusive of transcriptomics, metabolomics, or other methodologies that address downstream consequences in gene regulation, protein expression, or metabolites in response to the null mutation.  A focus on specified organs or systems is acceptable to control costs but in general, the approach should be broad and not limited to single organs.

All phases of the phenotyping process must be addressed as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well as proposed solutions;

iii. cost breakdowns of assays or groups of assays by lines analyzed;

iv. timelines and quantitative milestones where appropriate

Adult Phenotyping: The applicant should propose a phenotyping pipeline that will characterize mice at later ages (at least one year and up to eighteen months of age). Issues to be addressed include, but are not limited to, selection of knockout strains to be aged (up to 20% of the strains), time points for phenotyping, and assays to be performed at some or all of these time points. As such, the application should describe modifications to standard IMPC phenotyping assays, the size of cohorts needed, and the source and numbers of wild type mice needed for controls. The applicant should describe previous experience with aging cohorts.

All phases of the phenotyping process must be addressed as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well as proposed solutions;

iii. cost breakdowns of assays or groups of assays by lines analyzed;

iv. timelines and quantitative milestones where appropriate

Quality Control: The applicant should discuss any means that will be taken to determine and ensure the quality of, or otherwise validate, the resources that will be generated, beyond those mentioned above. Examples of appropriate quality control procedures include those for validation of phenotyping procedures and data, such as quality control of assays and data collection. The application should include QC procedures for each assay employed in the phenotyping platforms and the frequency of the QC. Examples of appropriate quality control procedures include those for confirmation of the targeted allele, periodic validation of equipment and assays, data integrity, data validity, and testing the pathogen status of all biological reagents. Evidence of and experience in the effectiveness of the proposed quality control programs should be included.

IT Requirements: The applicant should discuss all pertinent informatics issues. These include, but are not limited to, the informatics infrastructure of the phenotyping systems, such as the basic IT infrastructure/system administration, the laboratory information management system, and the system for data handling and deposition. It is vital that the phenotyping data be provided in a format that can be easily uploaded to the DCC. The application should describe activities related to the timely uploads of the data in a standardized format, subsequent coordination/communication with data wranglers at the DCC and with the statistics working group. The applicant should describe a process to resolve issues, with the goal of improving data throughput.

Technology Development:  Incremental technology improvements will play an important role in increasing the efficiency and decreasing the cost of high-throughput phenotyping of mouse knockouts. Providing phenotypic information that is accurate, sensitive, reliable and reproducible is critical to gain a better understanding of the relationship between genes and phenotypes. The proposal should describe the applicant’s efforts to use modern automated technologies and methodologies for phenotypic assays with a goal to generate a large number of measurements using a limited number of animals. The full potential of laboratory techniques that can be adaptable to high-throughput procedures should be explored.

D) Research Management Plan

The proposal should describe a management plan commensurate with the complexity of this effort, including integration of the separate components to maintain an efficient operation, key personnel, section leaders and internal reporting relationships and mechanisms for reporting progress to NHGRI and ORIP/DPCPSI (see Terms and Conditions, below) as well as the decision-making process. Include how this management plan will support achievement of the proposed goals and milestones of the project and will involve regular evaluation of production and phenotyping and scientific progress.  The proposed management plan should ensure appropriate prioritization of activities, including a process to reallocate resources as needed, and should describe how problems will be identified and resolved, should encourage and provide training for personnel, and should enhance the visibility and effectiveness of the efforts. This section should also describe in detail the progress tracking of the production and phenotyping pipelines. This section should discuss initiation and coordination of projects in collaboration with the research network, the community, and the ability to track and report on multiple projects from gene selection through the completion of analysis. This section should also describe general features of how projects will be initiated in collaboration with the community, and any general structures or resources in place for enhancing collaborations. The management plan should discuss past experiences working in large collaborative data production projects of a degree of complexity similar to what is being requested.

The center should describe its participation in and contribution to the KOMP2 Committees, Subcommittees, and the KOMP2 teleconferences and Annual Meeting. The PD/PI of the center is expected to serve as a regular member of the IMPC Steering Committee. The PD/PI and other key personnel are required to attend the KOMP2 Annual Meeting. Center staff should attend other subcommittee meetings, attend open video conferencing, and provide general assistance to the subcommittees that will be put in place aid KOMP2 management and organization.

The application should also describe the plans for evaluation of progress and communication strategies to manage and track progress of the activities and services. The center should actively participate in KOMP2 and IMPC program evaluation activities including progress reports, site visits, and additional communication and materials to the NIH as needed.  The application should address how the identification and proposed resolution of problems and engagement with the NIH Staff will take place as appropriate.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan, or explain why data sharing is not possible. 

Resource Sharing Plan.  Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible. NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community (https://grants.nih.gov/grants/policy/).  It is highly likely that software solutions and LIMS system development would benefit the other IMPC phenotyping centers as well as other investigators. Therefore, the applicant's data release plan should address how software or laboratory technology improvements developed under this funding will be publicly released. Applicants should not feel constrained to propose a standard plan for sharing materials, given the scope of KOMP2 as defined by the FOA and the NIH's investment in this project. Widespread dissemination and access to the materials generated through this program to the public and private research sectors are an aim of this FOA and will require innovative methods for achieving the maximum use of the resource to be produced under this project.

Data Sharing Plan. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.  In the case of phenotypic data, plans for the dissemination and access of the data through a centralized database are needed, in line with the aims of the FOA.  With regard to the present FOA, NIH has identified the goal of the KOMP2 as the production of “community materials” as described in the proceedings of the Meeting on Sharing Data from Large-Scale Biological Research Projects (https://www.genome.gov/Pages/Research/WellcomeReport0303.pdf). Therefore, responses to this FOA should propose a specific and comprehensive plan for the rapid release of data resulting from the knockout mouse production and phenotyping effort to the appropriate databases. Rapid release of the data to the scientific user community is a goal of the KOMP2 project, because of the scope of this community resource project as described in this FOA and because of the national and scientific investment that the NIH will make in KOMP2. Accordingly, applicants should not feel constrained by the standard approach to data sharing but should display and promote innovative methods for achieving the maximum use of the KOMP2 resource.

Sharing Model Organisms Plan.   As the production of gene knockout mice, frozen sperm and embryos are an integral part of the KOMP2 project, all applicants are expected to include a description of a specific plan for sharing and distributing unique model organisms or state why such sharing is restricted or not possible.  It is expected that mutant mouse strains created for this project will be deposited at the Mutant Mouse Regional Resource Center (MMRRC) repositories for further distribution. To enable ready access to these materials, a uniform MTA such as the Simple Letter Agreement (SLA) or Condition of Use statement is preferred for all recipients who receive resources made by this effort to ensure that the resources made by this initiative are available in a manner consistent with the goals of this FOA and with no additional reach-through rights to inventions/discoveries made by the end users. Although NIH Policy strongly discourages the patenting of research resources, applicants are free to patent their discoveries so long as the embryos, mice, and data are made available for research purposes in a manner consistent with the NIH Data Sharing Policy, other NIH sharing policies (http://grants.nih.gov/grants/sharing.htm), and achieving the goals of this FOA.

Authorization and Consent

(a) The Government authorizes and consents to all use and manufacture of any invention described in and covered by a United States patent in the performance of this Cooperative Agreement at all tiers.

Notice and Assistance Regarding Patent and Copyright Infringement.

(b) The Grantee shall report to the Program Director, promptly and in reasonable written detail, each notice or claim of patent or copyright infringement based on the performance of this Cooperative Agreement of which the Grantee has knowledge.

(c) In the event of any claim, suit, threat of a claim or suit, or in the event that a patent-owner alleges the relevance of a patent and the Government agrees to enter into discussions related thereto, on account of any alleged patent or copyright infringement arising out of the performance of this Cooperative Agreement against the Government or out of the use of any supplies furnished or work or services performed under this Cooperative Agreement, the Grantee shall furnish to the Government, when requested by the Program Director, all evidence and information in possession of the Grantee pertaining to such suit or claim. Such evidence and information shall be furnished at the expense of the Government except where the Grantee has agreed to indemnify the Government.

(d) The Grantee agrees to include, and require inclusion of, this clause in all sub-awards and subcontracts at any tier for supplies or services (including construction and architect-engineer sub-awards and subcontracts and those for material, supplies, models, samples, or design or testing services). 

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award".

Appendix:  Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide. 

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information
1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?  In addition to the standardized criteria above, the following will be evaluated as part of the Significance score. Does the center serve the needs of investigators in a variety of research areas rather than in a single or few areas? Will the project resources be available to investigators on a local, regional, and national basis?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?  In addition to the standardized criteria above, the following will be evaluated as part of the Investigator(s) score.  Are the PD(s)/PI(s) appropriately trained and well suited to manage such a large and complex project? 

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?  In addition to the standardized criteria above, the following will be evaluated as part of the Innovation score. Is the overall design of the center, mouse production and cryopreservation as well as phenotyping pipeline innovative? Does the application utilize innovative approaches to rapidly provide the project data and resources to the biomedical community?  Is the technology development aspect of the application innovative?    

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? In addition to the standardized criteria above, the following will be evaluated as part of the Approach score. Are the organization, management structure, integration of the components, key personnel and reporting relationships well described and appropriate? Is the project well integrated with the broad based phenotyping activity of the KOMP2 research network? Are adequate approaches proposed for enhancement of the capacity to utilize innovative technologies and improve the efficiency of generating phenotyping data?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?  

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?  In addition to the standardized criteria above, the following will be evaluated as part of the Environment score. Is there appropriate Institutional Support for the project, and are plans for continuity appropriate for the scientific field’s needs? Is the form of this commitment (space, resources) appropriate? Is there evidence of project participation in coordination and integration of its activity with other KOMP2 centers as well as other members of IMPC?   

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Review Criteria for Animal Production and Cryopreservation Section

The Animal Production and Cryopreservation Section will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects the following:

  • Does the PD/PI provide evidence of team experience in reliable, high-throughput production of high-quality knockout strains and their cryopreservation?
  • Do preliminary results with use of CRISPRs/Cas9 technology to generate knockout strains indicate sufficient experience of the team, and do the results demonstrate advantages in comparison to traditional use of ES cells?
  • Are strategies for the target gene selection described in detail and will the approach support generation of the required number of knockout mouse lines per year?
  • Does the application have clear descriptions of the procedures for efficient generation of defined deletions in N1 mice, design of guide RNAs, microinjection procedures, mutation screening methods, animal breeding schemes, and workflows for scaled mouse production?
  • Is the plan for assessment and statistical analysis of embryonic lethality, fertility and fecundity of homozygous mice included and adequate to support the goals of the project?
  • Are plans and procedures for establishing and expanding breeding colonies to produce homozygous or heterozygous (for lethal or subviable strains) mice and providing them as live cohorts to phenotyping pipeline described?
  • Are explicit production milestones and timelines provided?
  • How well are pertinent informatics issues presented, including the informatics infrastructure of the production system such as the basic IT infrastructure/system administration, the laboratory information management system, and the system for data handling and deposition?
  • What measures will be taken to ensure that the production data are provided in a format that can be easily uploaded to the DCC and that production data will include sufficient tracking information?
  • Is the proposed method to determine and ensure the quality of, or otherwise validate, the resources that will be generated adequate?
  • Are the QC tests for embryo or sperm cryopreservation and cryo-recovery well described and will they ensure the required preservation of the generated resources?
  • Are proposed animal husbandry conditions and approaches to monitoring animal health well described and adequate?
  • Is it likely that technology improvements described in this section will increase the efficiency and decrease the cost of high-throughput production processes?

Review Criteria for Phenotyping Section

The Phenotyping Section will receive a merit descriptor (outstanding, acceptable, unacceptable) for the following:

  • Is evidence provided that the PDs/PIs have sufficient experience in high-throughput phenotyping of knockout strains?
  • Is expertise or training of staff, relevant to performing phenotyping assays, described and adequate?
  • Is evidence provided that the phenotyping tests are harmonized with international efforts and do the centers appear to have flexibility to add, modify or drop tests as the project progresses?
  • Are cost benefit analyses of the phenotyping assays included and is the rationale for inclusion or exclusion of assays from the current pipeline well justified?
  • Is the general strategy on how to characterize mouse phenotypes at later ages, including the selection of knockout strains to be aged (up to 20% of the strains), time points for phenotyping, and assays to be performed at some or all of these time points, described in sufficient detail? Is the plan reasonable and likely to be successful?
  • Are quality control procedures, such as those for validation of phenotyping results and data integrity, validation of equipment, and testing the pathogen status of mice, well described and adequate?
  • Does the PD/PI discuss in sufficient detail the pertinent informatics issues, including informatics infrastructure for colony management and tracking, the laboratory information management system, and the system for data handling and deposition to the DCC?
  • Are technology development approaches that may increase the efficiency and decrease the cost of the high-throughput phenotyping of mouse knockouts adequately described?

Review Criteria for Research Management Plan Section

The Research Management Plan Section will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects the following:

  • Is the proposed management plan commensurate with the complexity of the effort, including integration of the separate components to maintain efficient operation, key personnel, section leaders, internal reporting relationships and mechanisms for reporting progress to NHGRI and ORIP/DPCPSI (see Cooperative Agreement Terms and Conditions, below)?
  • Is there a plan for regular internal evaluation of production and phenotyping?
  • Is the decision making process clear and rational?
  • Does the proposed plan include prioritization of activities, such as resource reallocations as needed, a process to identify and resolve problems, a plan to encourage and provide training for personnel, and a means to enhance visibility and effectiveness of the efforts?
  • Are the proposed processes to track and report on multiple projects (from gene selection through completion of analysis) well described and adequate?
  • Is the plan to coordinate with the IMPC well described and adequate?
  • Does the plan adequately address evaluation activities, including progress reports, site visits, and additional communication and materials to the NIH as needed?  
Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Human Genome Research Institute, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

  • Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned  to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council, which is the National Advisory Council for Genome Research Institute or the NIH Council of Councils for the Office of Research Infrastructure Programs. The following will be considered in making funding decisions:

  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.
3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information
1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

  • Defining the details for the gene knockout production project within the guidelines of FOA RFA-RM-15-017 and for performing the scientific activities;
  • Collaborating with the other members of the KOMP2 Research Network;
  • Determining experimental approaches, design protocols, set project milestones and conduct experiments;
  • Endeavoring to meet or exceed stated milestones;
  • Accepting and participating in the cooperative nature of the KOMP2 Research Network;
  • Serving, along with the PI of each of the other funded KOMP2 Research Network awards, on the Steering Committee for the KOMP2 Research Network; the P.I. will have one vote on the Steering Committee;
  • Providing goals for throughput, quality, and cost as requested (usually at the outset of the award and in monthly progress reports to the Steering Committee, but also at other times as requested by NIH program staff);
  • Ensuring that the products of the production effort meet or exceed the quality standards and costs agreed upon at the time of award;
  • Submitting data for quality assessment in any manner specified by the Steering Committee or the Panel of Scientific Consultants;
  • Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and the Panel of Scientific Consultants;
  • Ensuring that the data are deposited in the appropriate public databases (e.g., the grantee to be funded by RFA-RM-15-016, as specified by NHGRI program staff), and that resources developed as part of this project are made publicly available through an NIH-designated repository according to NIH policies;
  • Adhering to the general NIH policies regarding sharing resources, data release, and resource sharing, as well as the specific data and resource-sharing policies proposed in the application, as modified by any negotiation prior to award or that might be established by the Steering Committee during the course of this activity;
  • Accepting and implementing any other common policies, guidelines and procedures that are developed and approved for the KOMP2 by the Steering Committee and the Panel of Scientific Consultants;
  • Coordinating and collaborating with other U.S. and international groups producing mouse knockout mutants as a community resource;
  • Informing the NIH Program Director of all major interactions with members of the Steering Committee;
  • Attending a yearly Steering Committee meeting with the Panel of Scientific Consultants;
  • Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:The NIH Project Scientist will:

  • Assist and facilitate the group process and not direct it;
  • Participate (with the PI and the other Steering Committee members) in the group process of setting research priorities for the KOMP2 Research Network, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted;
  • Negotiate goals for throughput, quality, and cost with the awardee, as necessary;
  • Serve as a liaison between the awardee and the Panel of Scientific Consultants, the National Advisory Council for Human Genome Research, and other national advisory councils or boards;
  • Coordinate the efforts of the awardee with other participants in the KOMP2 and IMPC programs, including other awardees under this FOA, with any other large-scale knockout efforts in the U.S., with international mouse knockout projects, and with the larger biological research community;
  • Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
  • Periodically report progress to the NIH Knockout Mouse Working Group, the Director of NHGRI, the Director of DPCPSI and the Directors of the NIH Institutes supporting the KOMP2;
  • Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Panel of Scientific Consultants and the Steering Committee;
  • Serve as liaison between the Steering Committee and the Panel of Scientific Consultants;
  • Serve on subcommittees of the Steering Committee, as appropriate; to provide advice in the management and technical performance of the investigation;
  • Assist in promoting the availability of the mouse knockout mutants and related materials and resources developed in the course of this project to the scientific research community-at large;
  • Participate in data analyses, interpretations, and where warranted, authoring of the publication of results of studies conducted as part of the KOMP2 Research Network;
  • Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
  • Retain the option to recommend, with the advice of the Panel of Scientific Consultants, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, or fails to maintain the state of the art in the production of mouse knockout mutants or fails to comply with the Terms and Conditions of the award.
  • Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

All components of the KOMP2 program will be funded by cooperative agreements and a single Steering Committee and a single Panel of Scientific Consultants will serve for all of the KOMP2 activities. The Steering Committee will serve as the main governing board of the KOMP2 Research Network. The Steering Committee membership will include the PI of each awarded cooperative agreement and the NIH Project Scientist of each of the components of the KOMP2 Research Network. Additional members may be added by action of the Steering Committee. Members of the KOMP2 Working Group may attend the Steering Committee meetings. Government employees outside of KOMP2 Working Group members may also attend, if their expertise is required for specific discussions.

The Steering Committee will:

  • Discuss progress in meeting the goals of the KOMP2 to provide a comprehensive collection of phenotyped null mutant mice to the research community;
  • Discuss potential modifications of the goals of the KOMP2 in light of developing technology and any changes in the scientific community's need for phenotyped mouse knockout mutants;
  • Develop recommendations for uniform procedures and policies necessary to meet the goals of the KOMP2, for example for data quality measures and assessment, nomenclature and annotation conventions for data deposition, for the KOMP2 Research Network. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the KOMP2 Working Group and the Panel of Scientific Consultants;
  • Serve as a venue for coordination on the improvement of mouse knockout phenotype production, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies;
  • Interact as an active member with the IMPC

Each full member will have one vote; the total votes of the NIH Project Scientist-members of the Steering Committee will constitute a minority of the votes. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Panel of Scientific Consultants:

This program will be coordinated with and be a member of the IMPC. The IMPC and KOMP2 shall convene a joint Panel of Scientific Consultants (PSC). The

PSC will be responsible for reviewing and evaluating the progress of the members of the KOMP2 Research Network toward meeting their individual and collective goals. The PSC will provide recommendations to the KOMP2 Working Group and the Directors of all of the other participating institutes, about continued support of the components of the KOMP2 Research Network. The Panel will be composed of four to six senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in the KOMP2 Research Network. The membership of the Panel of Scientific Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The PSC will meet at least once a year and by conference call 2 to 3 times per year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the PSC members to interact directly with the awardees. Annually, the PSC will make recommendations to the NIH

regarding progress of the KOMP2 Research Network and present advice about changes, if any, which may be necessary in the KOMP2 Research Network program to the relevant NIH Directors.

The KOMP2 Working Group consists of program staff from each of the NIH institutes supporting the KOMP2. The purpose of the KOMP2 Working Group will be to disseminate information about the progress of the KOMP2 Research Network to the participating Institutes and to provide a forum for the participating Institutes to discuss issues related to KOMP2. The KOMP2 Working Group members will report to the Director of their respective IC.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for aiitional information on this reporting requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Scientific/Research Contact(s)

Colin Fletcher, Ph.D.
National Institute of Human Genome Research (NHGRI)
Telephone: 301-496-7531
Email: fletcherc2@mail.nih.gov

Oleg Mirochnitchenko, Ph.D.
Office of Research Infrastructure Programs (ORIP)
Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI)
Telephone: 301-435-0748
Email: mirochnitcheno@mail.nih.gov

Peer Review Contact(s)

Ken Nakamura
Office of Scientific Review
National Human Genome Research Institute (NHGRI)   
Telephone: (301) 496-7531
Email: nakamurak@mail.nih.gov

Financial/Grants Management Contact(s)

Monika Christman
National Human Genome Research Institute (NHGRI)
Telephone: 301-435-7860 
Email: christmm@exchange.nih.gov

Melissa Austin Williams, MP
National Center for Advancing Translational Sciences (NCATS)
Phone: 301-402-7183
Email: melissa.austin@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.

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